A variety of different optical biopsy techniques have been described and developed for a non-invasive diagnosis of disease within living human patients. While these conventional devices can provide information that is related to disease, there are differences between the data obtained by these prior art methods and the medical standards of care for diagnosis.
Pathologists generally diagnose tissues based on a microscopic visualization of Hematoxylin & Eosin (H&E) stained slides and a morphological interpretation thereof. Pathologists may employ scoring systems or techniques, in which a variety of features are noted and formed to render a diagnosis. These scoring systems or techniques can standardize and provide a quantitative or semi-quantitative basis for diagnosis. Examples of such scoring systems and techniques include a Gleason grade for prostate adenocarcinoma, Haggitt's criteria for dysplasia in Barrett's esophagus, Banff kidney allograft scoring system, Nash scoring system for nonalcoholic fatty liver disease. Other scoring systems and techniques for such diagnosis exist.
Preferably, a unique relationship can be established between the optical biopsy information and the techniques and scoring systems that for the basis of the standard of care. In turn, the same criteria are generally used to render the diagnosis for the standard of care can then be utilized, in a modified form, on the optical biopsy diagnostic information. In turn, a modified scoring system or technique based on features identified in the optical biopsy images may be implemented to diagnose tissue in a manner consistent with the histopathology standard of care.
Provided below are examples of upper gastrointestinal scenarios which may be pertinent to Barrett's esophagus, where optical biopsy images can be utilized to render a diagnosis.
Diagnosing Specialized Metaplasia at the Gastroesophageal Junction
Gastroesophageal reflux disease (GERD) is increasing in incidence, and is a well-known risk factor for the development of esophageal specialized intestinal metaplasia (SIM), commonly known as Barrett's esophagus (BE), as described in R. J. Loffeld et al. “Rising incidence of reflux oesophagitis in patients undergoing upper gastrointestinal endoscopy” Digestion, 2003, Vol. 68(2-3) pp. 141-4. The prevalence of SIM has been estimated to be as high as 10-15% in patients with chronic GERD as discussed in C. Winters, Jr. et al., “Barrett's esophagus. A prevalent, occult complication of gastroesophageal reflux disease. Gastroenterology,” 1987, Vol. 92(1), pp. 118-24. For a patient with recurrent and severe symptoms of GERD, the adjusted odds ratio for developing adenocarcinoma over a 20-year period is 7.7 and 43.5, respectively, as described in J. Lagergren et al., “Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma,” N Engl J Med, 1999, Vol. 340(11), pp. 825-31. Moreover, the incidence of esophageal adenocarcinoma and proximal stomach (gastric cardia) cancers has rapidly increased in the last 30 years, as discussed in W. J. Blot et al., “Rising incidence of adenocarcinoma of the esophagus and gastric cardia,” Jama, 1991, Vol. 265(10), pp. 1287-9; P. Bytzer et al., “Adenocarcinoma of the esophagus and Barrett's esophagus: a population-based study,” Am J Gastroenterol, 1999, Vol. 94(1), pp. 86-91; and S. S. Devesa et al., “Changing patterns in the incidence of esophageal and gastric carcinoma in the United States,” Cancer, 1998, Vol. 83(10), pp. 2049-53.
Due to the recognition of GERD as possible a risk factor for developing esophageal cancer, upper endoscopic screening can be recommended, e.g., for white, male patients older than 50 years who have chronic symptoms of GERD for more than 5 years, as discussed in S. J. Spechler, “Screening and surveillance for complications related to gastroesophageal reflux disease,” Am J Med, 2001, Vol. 111 Suppl 8A, pp. 130S-136S. As a result of the increasing prevalence of GERD and the medical community's recognition of SIM as a risk factor for esophageal cancer, the use of endoscopy as a screening strategy for SIM will likely increase significantly in the near future. Such increases may incur significant costs to the health care system and to the individual patient. Other screening methods that could provide greater area coverage than conventional biopsy may reduce the risk and inconvenience of multiple endoscopic procedures. Furthermore, certain methods which do not utilize endoscopy can potentially be conducted at a lower cost, partially alleviating the financial burden of comprehensive screening on the health care system.
Identifying Dysplasia in Patients with Barrett's Esophagus
When BE is diagnosed, a periodic endoscopic surveillance to detect HGD may be recommended. These recommendations can proceed from observations noting the high incidence (25% over 46 months) of adenocarcinoma in patients with HGD, as described in P. Sharma et al., “A critical review of the diagnosis and management of Barrett's esophagus: the AGA Chicago Workshop,” Gastroenterology, 2004, Vol. 127(1), pp. 310-30. Current guidelines for surveillance of HGD can include four-quadrant biopsies every two centimeters along the axial length of the Barrett's segment, as discussed in D. S. Levine et al., “An endoscopic biopsy protocol can differentiate high-grade dysplasia from early adenocarcinoma in Barrett's esophagus,” Gastroenterology, 1993, Vol. 105(1), pp. 40-50. The accuracy of surveillance endoscopy, however, may be limited by a sampling error, as discussed in G. S. Dulai, “Surveying the case for surveillance,” Gastroenterology, 2002, Vol. 122(3), pp. 820-823; G. W. Falk et al., “Surveillance of patients with Barrett's esophagus for dysplasia and cancer with balloon cytology,” Gastroenterology, 1997, Vol. 112(6), pp. 1787-1797; and J. M. Streitz et al., “Endoscopic surveillance of Barrett's esophagus. Does it help?” Journal of Thoracic and Cardiovascular Surgery, 1993, Vol. 105, pp. 383-388. The optimal surveillance and screening strategies for BE are discussed, but many cost-effectiveness analyses focus on frequency and costs of endoscopy as key determinants, as described in J. W. van Sandick et al., “Impact of endoscopic biopsy surveillance of Barrett's oesophagus on pathological stage and clinical outcome of Barrett's carcinoma,” Gut, 1998, Vol. 43(2), pp. 216-22; J. M. Inadomi et al., “Screening and surveillance for Barrett esophagus in high-risk groups: a cost-utility analysis,” Ann Intern Med, 2003, Vol. 138(3), pp. 176-86; D. Provenzale et al., “Barrett's esophagus: a new look at surveillance based on emerging estimates of cancer risk,” Am J Gastroenterol, 1999, Vol. 94(8), pp. 2043-53; and A Sonnenberg et al., “Medical decision analysis of endoscopic surveillance of Barrett's oesophagus to prevent oesophageal adenocarcinoma,” Aliment Pharmacol Ther, 2002, Vol. 16(1), pp. 41-50.
Due to the increasing prevalence of GERD and the medical community's recognition of BE as a risk factor for esophageal cancer, use of endoscopy as a screening and surveillance strategy for BE will increase significantly in the near future. Such increases can incur significant costs to the health care system and to the individual patient. Potential low cost surveillance strategies can include certain endoscopic technologies such as narrow band imaging, chromoendoscopy, or fluorescence endoscopy. Non-endoscopic imaging modalities may also play a role in the management of BE. Methods for directing biopsies to regions of the esophagus containing dysplastic tissue could improve the effectiveness and efficiency of surveillance in patients with BE by increasing surveillance intervals, enabling minimally invasive surgical techniques at an earlier stage of disease progression, or preventing unnecessary interventional procedures.
Provided below is an example of one such optical biopsy technique that can be utilized to obtain information from living human patients.
Optical Coherence Tomography
Optical coherence tomography (OCT) is an optical imaging modality that can use, e.g., a near-infrared light to produce high-resolution (10 μm axial resolution) cross-sectional images of gastrointestinal mucosa. Images may be constructed based on light reflectivity in relation to the properties of the substrate being visualized. OCT techniques can be used to identify structures on a microscopic scale including mucosal layers, “pit and gland” morphology, and glandular structure, as described in S. Brand et al., “Optical coherence tomography in the gastrointestinal tract,” Endoscopy, 2000, Vol. 32(10), pp. 796-803. For example, the OCT techniques can distinguish SIM from squamous fundic, and antral mucosa but can falsely identify gastric cardia as SIM, as discussed in J. M. Poneros et al., “Diagnosis of specialized intestinal metaplasia by optical coherence tomography,” Gastroenterology, 2001, Vol. 120(1), pp. 7-12.
For the OCT techniques to be, e.g., a reliable sensitive and cost effective screening instrument, a characterization of epithelial architecture at the squamocolumnar junction should be accurate enough to distinguish premaligant (SIM) from benign tissue and to identify SIM at the SCJ. Algorithms and methods are required to obtain distinguish SIM from cardia at the SCJ and dysplastic from nonmetaplastic tissue at the gastroesophageal junction.
Described below is an example of the pathologic Haggitt criteria and techniques for diagnosing and grading dysplasia in SIM from H&E stained slides of esophageal biopsies. The Haggitt criteria may be used to aid in rendering a qualitative diagnosis or formulated as a scoring system for semi-quantitative or quantitative diagnosis.
Dysplasia is histologically characterized by, e.g., various degrees and combinations of cytologic atypia and architectural disarray (as described in R. C. Haggit, “Barrett's esophagus, dysplasia, and adenocarcinoma,” Human Pathology, 1994, Vol. 25, pp. 982-93, and E. Montgomery et al. “Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation,” Human Pathology. 2001, Vol. 32, pp. 368-378) for a histologic diagnosis of dysplasia in esophageal SIM. One exemplary set of criteria that can be noted by pathologists and used to render a diagnosis of dysplasia grade is known as the Haggitt criteria. These criteria may be used as part of a scoring system or may be used in a qualitative algorithm for more consistent diagnosis of dysplasia grade. Each of the four Haggitt features are listed below, as described in Montgomery et al. “Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation,” Human Pathology. 2001, Vol. 32, pp. 368-378.
A) Gland Architecture
Glands of dysplastic SIM can be crowded, distorted and irregular in contour with budding, branching, and luminal infoldings. Cribiform glands, cystic dilation, and necrotic debris are more likely to be identified in severe dysplasia.
B) Surface Maturation in Comparison with Underlying Glands
Nondysplastic SIM may have the greatest degree of surface maturation, while HGD can have minimal surface maturation. A high degree of surface maturation implies a low nuclear-to-cytoplasmic ratio at the surface, whereas a low degree of surface maturation indicates a high surface nuclear-to-cytoplasmic ratio.
3) Nuclear Atypia
Cells within dysplastic epithelia generally contain enlarged, hyperchromatic nuclei with irregular nuclear membranes, vesicular (heterogeneous) chromatin, and a loss of nuclear polarity.
4) Inflammation
Inflammation is a confounding factor in the diagnosis of dysplasia since it can independently give rise to distorted glandular architecture and nuclear atypia. Cases where architectural and nuclear atypia may be a result of inflammation are termed indefinite for dysplasia (IND). The interobserver agreement for this diagnosis by histology is low (κ=0.14) (as described in Montgomery et al. “Reproducibility of the diagnosis of dysplasia in Barrett esophagus: a reaffirmation,” Human Pathology. 2001, Vol. 32, pp. 368-378) as it is often reserved for cases where artifacts obscure features required to render a definitive diagnosis or when multiple criteria from different ends of the disease spectrum are simultaneously present.